U.S. patent application number 12/554235 was filed with the patent office on 2010-03-11 for pharmaceutical combination.
This patent application is currently assigned to GRUENENTHAL GmbH. Invention is credited to Petra Bloms-Funke, Thomas Christoph, Klaus Schiene.
Application Number | 20100063148 12/554235 |
Document ID | / |
Family ID | 40345058 |
Filed Date | 2010-03-11 |
United States Patent
Application |
20100063148 |
Kind Code |
A1 |
Christoph; Thomas ; et
al. |
March 11, 2010 |
Pharmaceutical Combination
Abstract
A composition of matter comprising in combination as component
(a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
compound, and as component (b) at least one antiepileptic, a
pharmaceutical formulation and a dosage form comprising said
composition of matter, and a method of treating pain, e.g.
neuropathic pain, in which components (a) and (b) are administered
simultaneously or sequentially to a mammal, whereby component (a)
may be administered before or after component (b) and whereby
components (a) or (b) are administered to the mammal either via the
same or a different pathway of administration.
Inventors: |
Christoph; Thomas; (Aachen,
GB) ; Schiene; Klaus; (Juechen, DE) ;
Bloms-Funke; Petra; (Wuerselen, DE) |
Correspondence
Address: |
CROWELL & MORING LLP;INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
GRUENENTHAL GmbH
Aachen
DE
|
Family ID: |
40345058 |
Appl. No.: |
12/554235 |
Filed: |
September 4, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61094787 |
Sep 5, 2008 |
|
|
|
Current U.S.
Class: |
514/561 ;
514/654 |
Current CPC
Class: |
A61K 31/137 20130101;
A61P 43/00 20180101; A61P 25/08 20180101; A61P 35/00 20180101; A61P
25/06 20180101; A61P 29/00 20180101; A61P 25/04 20180101; A61P
25/00 20180101; A61K 45/06 20130101; A61K 31/137 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/561 ;
514/654 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 31/197 20060101 A61K031/197; A61P 25/00 20060101
A61P025/00; A61P 25/08 20060101 A61P025/08 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 5, 2008 |
EP |
08 015 625.0 |
Claims
1. A composition of matter comprising in combination: (a) a
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound
corresponding to formula (I): ##STR00003## or a pharmaceutically
acceptable salt thereof, and (b) at least one antiepileptic.
2. A composition of matter as claimed in claim 1, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is
present in the form of an isolated stereoisomer.
3. A composition of matter as claimed in claim 1, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is
present in the form of a mixture of stereoisomers in any mixing
ratio.
4. A composition of matter as claimed in claim 3, wherein said
mixture is a racemic mixture.
5. A composition of matter as claimed in claim 1, wherein the
compound of formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
mixtures of two or more of the foregoing.
6. A composition of matter as claimed in claim 5, wherein said
compound of formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
mixtures thereof.
7. A composition of matter as claimed in claim 6, wherein said
compound of formula (I) is
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of
formula (I'), ##STR00004## or an acid addition salt thereof.
8. A composition of matter as claimed in claim 7, wherein said
compound of formula (I) is a hydrochloride salt of
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.
9. A composition of matter as claimed in claim 1, wherein the
antiepileptic is selected from the group consisting of
methylphenobarbital, phenobarbital, primidone, barbexaclone,
metharbital, ethotoin, phenytoin, amino(diphenylhydantoin)valeric
acid, mephenytoin, fosphenytoin, paramethadione, trimethadione,
ethadione, ethosuximide, phensuximide, mesuximide, clonazepam,
carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, valproic
acid, valpromide, aminobutyric acid, vigabatrin, progabide,
tiagabine, sultiame, phenacemide, lamotrigine, felbamate,
topiramate, gabapentin, pheneturide, levetiracetam, brivaracetam,
selectracetam, zonisamide, pregabalin, stiripentol, lacosamide,
beclamide, mexiletin, retigabin and ralfinamide.
10. A composition of matter as claimed in claim 9, wherein the
antiepileptic is selected from the group consisting of pregabalin,
gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin,
lacosamide, phenytoin, levetiracetam, retigabin, valproic acid and
ralfinamide.
11. A composition of matter as claimed in claim 1, wherein the two
components (a) and (b) are present in the form of a salt formed
from said two components.
12. A composition of matter as claimed in claim 1, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or salt
thereof and said antiepileptic are present in a weight ratio such
that the composition exerts a synergistic effect upon
administration to a patient.
13. A composition of matter as claimed in claim 1, further
comprising at least one pharmaceutical carrier or auxiliary
agent.
14. A composition of matter as claimed in claim 13, wherein said
composition is formed into a dosage form suitable for oral,
intravenous, intraarterial, intraperitoneal, intradermal,
transdermal, intrathekal, intramuscular, intranasal, transmucosal,
subcutaneous, or rectal administration.
15. A composition of matter as claimed in claim 14, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or said
antiepileptic, or both, is present in controlled-release form.
16. A composition of matter as claimed in claim 13, wherein said
composition comprises caffeine.
17. A method of treating or inhibiting pain in a subject in need
thereof, said method comprising administering to said subject a
pharmacologically effective amount of a composition as claimed in
claim 1.
18. A method as claimed in claim 17, wherein said pain is selected
from the group consisting of inflammatory pain, neuropathic pain,
acute pain, chronic pain, visceral pain, migraine pain and cancer
pain.
19. A method as claimed in claim 17, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and
said antiepileptic are administered simultaneously either by the
same or by different pathways of administration.
20. A method as claimed in claim 17, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and
said antiepileptic are administered sequentially either by the same
or by different pathways of administration, with the
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound being
administered before the antiepileptic.
21. A method as claimed in claim 17, wherein said
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and
said antiepileptic are administered sequentially either by the same
or by different pathways of administration, with the
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound being
administered after the antiepileptic.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from co-pending U.S.
provisional patent application No. 61/094,787, filed Sep. 5, 2008.
Priority is also claimed based on European patent application no.
EP 08 015 625.0, filed Sep. 5, 2008.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a combination comprising as
components (a) at least one
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and
(b) at least one antiepileptic, a pharmaceutical formulation and a
dosage form comprising said combination as well as a method of
treating pain, e.g. neuropathic pain, wherein components (a) and
(b) are administered simultaneously or sequentially to a mammal,
whereby component (a) may be administered before or after component
(b) and whereby components (a) or (b) are administered to the
mammal either via the same or a different pathway of
administration.
[0003] The treatment of chronic and acute pain conditions is
extremely important in medicine. There is currently a worldwide
demand for additional, not exclusively opioid-based, but highly
effective pain treatment. The urgent need for action for
patient-oriented and purposeful treatment of pain conditions, this
being taken to mean the successful and satisfactory treatment of
pain for the patient, is documented in the large number of
scientific papers which have recently appeared in the field of
applied analgesics and fundamental research work on
nociception.
[0004] Even if the analgesics that are currently used for treating
pain, for example opioids, NA- and 5HT-reuptake inhibitors, NSAIDS
and COX inhibitors, are analgesically effective, side effects
nevertheless sometimes occur. WO 01/13904 describes substance
combinations comprising a tramadol material and an anticonvulsant
drug, which show super-additive effects upon administration. Due to
the super-additive effect the overall dose and accordingly the risk
of undesired side effects can be reduced.
SUMMARY OF THE INVENTION
[0005] Thus, it was an object of the present invention to find
further combinations having improved properties. It was also an
object of the present invention to find further combinations that
are suitable for the treatment of pain and which preferably exhibit
fewer undesired side effects compared to its individual components,
if administered in effective doses.
[0006] It has been found that a combination comprising (a) at least
one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound,
and (b) at least one antiepileptic exhibits an analgesic effect. If
these components are present in the composition in such a weight
ratio that a supra-additive or synergistic effect is observed upon
administration to the patients, the overall administered dose may
be lowered, so that fewer undesired side-effects will occur.
[0007] Accordingly, the present invention relates to a
pharmaceutical combination comprising as components [0008] (a)
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula
(I)
[0008] ##STR00001## [0009] optionally in form of one of its pure
stereoisomers, in particular an enantiomer or a diastereomer, a
racemate or in form of a mixture of its stereoisomers, in
particular enantiomers and/or diastereomers in any mixing ratio, or
any corresponding acid addition salt thereof, and [0010] (b) at
least one antiepileptic.
[0011] In one embodiment of the inventive combination the compound
of formula (I) is selected from the group consisting of: [0012]
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, [0013]
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, [0014]
(1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, [0015]
(1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
[0016] any mixture thereof.
[0017] In another embodiment of the inventive combination the
compound of formula (I) is selected from [0018]
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
[0019] (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
and [0020] any mixture thereof.
[0021] In yet another embodiment the inventive combination
comprises [0022] (a) the compound
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of
formula (I'),
[0022] ##STR00002## [0023] or an acid addition salt thereof, and
[0024] (b) at least one antiepileptic.
[0025] The compound
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I),
its stereoisomers and corresponding salts thereof as well as
methods for their preparation are well known, for example, from
U.S. Pat. No. 6,248,737 B1, the entire disclosure of which is
incorporated herein by reference.
[0026] The definition of component (a) as used herein includes
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, derivatives
thereof and stereoisomers thereof in any possible form, thereby
particularly including solvates and polymorphs, salts, in
particular acid addition salts and corresponding solvates and
polymorphs.
[0027] The term derivative as used herein particularly includes
prodrugs such as ethers and esters of the active substance.
Suitable methods for selecting and preparing a pro-drug of a given
substance are for example described in "Textbook of Drug Design and
Discovery", 3.sup.rd edition, 2002, chapter 14, pages 410-458,
Editors: Krogsgaard-Larsen et al., Taylor and Francis. The
respective parts of said literature description are incorporated by
reference and form part of the present disclosure.
[0028] If component (a) is present as mixture of enantiomers, such
a mixture may contain the enantiomers in racemic or non-racemic
form. A non-racemic form could, for example, contain the
enantiomers in a ratio of 60.+-.5:40.+-.5, 70.+-.5:30.+-.5,
80.+-.5:20.+-.5 or 90.+-.5:10.+-.5.
[0029] The term "isolated" as used herein with regard to
stereoisomers (e.g., enantiomers or diastereomers) means that the
respective stereoisomer is separated from other stereoisomers but
not necessarily from other substances.
[0030] The compound
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and its
stereoisomers according to component (a) may be present in the
inventive pharmaceutical composition in form of an acid addition
salt, whereby any suitable acid capable of forming such an addition
salt may be used.
[0031] The conversion of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into a
corresponding addition salt, for example, via reaction with a
suitable acid may be effected in a manner known to persons skilled
in the art. Suitable acids include, but are not limited to,
hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, oxalic acid, succinic acid,
tartaric acid, mandelic acid, fumaric acid, lactic acid, citric
acid, glutamic acid and/or aspartic acid. Salt formation is
preferably effected in a solvent, for example, diethyl ether,
diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.
Moreover, trimethylchlorosilane in aqueous solution is also
suitable for the preparation of hydrochlorides.
[0032] Antiepileptics, which are often also referred to as
anticonvulsants, are well known in the art and include, without
limitation, barbiturates and derivatives, such as
methylphenobarbital, phenobarbital, primidone, barbexaclone and
metharbital; hydantoin derivatives such as ethotoin, phenytoin,
amino(diphenylhydantoin)valeric acid, mephenytoin and fosphenytoin;
oxazolidine derivatives such as paramethadione, trimethadione and
ethadione; succinimide derivatives such as ethosuximide,
phensuximide and mesuximide; benzodiazepine derivatives such as
clonazepam; carboxamide derivatives such as carbamazepine,
oxcarbazepine, eslicarbazepine and rufinamide; fatty acid
derivatives such as valproic acid, valpromide, aminobutyric acid,
vigabatrin, progabide and tiagabine; or other antiepileptics such
as sultiame, phenacemide, lamotrigine, felbamate, topiramate,
gabapentin, pheneturide, levetiracetam, brivaracetam,
selectracetam, zonisamide, pregabalin, stiripentol, lacosamide and
beclamide.
[0033] These afore mentioned classes of antiepileptics and most of
their individual representatives are, for example, listed in the
Anatomical Therapeutic Chemical (ATC) classification under [N03] as
used by the WHO for classification of pharmaceutically active
ingredients (preferred edition: January 2008 or 2009). With regard
to further details of the ATC-index reference is made to U. Fricke,
J. Gunther, Anatomisch-therapeutisch-chemische Klassifikation mit
Tagesdosen fur den deutschen Arzneimittelmarkt: Methodik der
ATC-Klassifikation and DDD-Festlegung. ATC-Index mit DDD-Angaben,
Wissenschaftliches Institut der AOK; and Swiss Pharmaceutical
Society, Index Nominum: International Drug Directory, CRC Press;
18th edition (Jan. 31, 2004). Other suitable antiepileptics
include, for example, mexiletin, retigabin and ralfinamide.
[0034] Some antiepileptics are known to be useful in the treatment
of neuropathic pain. In one embodiment of the present invention one
or more of these antiepileptics is used as component (b).
[0035] Also included are stereoisomers, salts, solvates, polymorphs
and derivatives of the antiepileptic component as well as mixtures
of any of the foregoing.
[0036] In one embodiment of the inventive combination the
antiepileptic according to component (b) is selected from the group
consisting of pregabalin, gabapentin, topiramate, lamotrigine,
carbamazepine, oxcarbamazepine, eslicarbazepine, mexiletin,
lacosamide, phenytoin, levetiracetam, brivaracetam, selectracetam,
retigabin, valproic acid and ralfinamide.
[0037] In another embodiment of the inventive combination the
antiepileptic according to component (b) is selected from the group
consisting of pregabalin, gabapentin, topiramate, lamotrigine,
carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam,
retigabin, valproic acid and ralfinamide.
[0038] In another embodiment of the inventive combination the
antiepileptic according to component (b) is pregabalin.
[0039] In yet another embodiment of the inventive combination the
antiepileptic according to component (b) is (S)-pregabalin.
[0040] A specific embodiment of the present invention is a
combination comprising (a)
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an
acid addition salt thereof such as the hydrochloride addition salt,
and (b) one or more antiepileptics selected from the group
consisting of pregabalin, gabapentin, topiramate, lamotrigine,
carbamazepine, oxcarbamazepine, eslicarbazepine, mexiletin,
lacosamide, phenytoin, levetiracetam, brivaracetam, selectracetam,
retigabin, valproic acid and ralfinamide.
[0041] A specific embodiment of the present invention is a
combination comprising (a)
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an
acid addition salt thereof such as the hydrochloride addition salt,
and (b) one or more antiepileptics selected from the group
consisting of pregabalin, gabapentin, topiramate, lamotrigine,
carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam,
retigabin, valproic acid and ralfinamide.
[0042] Another specific embodiment of the present invention is a
combination comprising (a)
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an
acid addition salt thereof such as the hydrochloride addition salt,
and (b) pregabalin.
[0043] Yet another specific embodiment of the present invention is
a combination comprising (a)
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an
acid addition salt thereof such as the hydrochloride addition salt,
and (b) (S)-pregabalin.
[0044] Some antiepileptics comprise functional groups, for example,
acidic groups such as carboxy groups which are capable of forming
salts with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
component of formula (I), thereby incorporating both components (a)
and (b) in one and the same salt. Thus, in another embodiment of
the present invention the inventive combination comprises
components (a) and (b) in form of a salt formed from these two
components. Such a salt formation may be partial, i.e. the
inventive composition comprises one or both of these components
also in their non-salt form, or the salt formation may essentially
be complete.
[0045] Both components (a) and (b) as part of the inventive
combination may be administered in amounts up to their maximum
daily dosage, which is known to those skilled in the art. The
compound Pregabalin may preferably be administered to a patient in
a daily dosage of 1 to 1200 mg, the compound Gabapentin may
preferably be administered to a patient in a daily dosage of 1 to
5000 mg. The compound
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol may
preferably be administered to a patient in a daily dosage of 25 to
1000 mg, particularly preferably in a dosage of 50 to 800 mg, more
particularly preferably in a dosage of 100 to 600 mg. When
administered as part of the inventive combination the administered
amount per day of component (a) and/or component (b) may be less
than the respective maximum daily dosage and be, for example,
75.+-.15 wt.-%, 75.+-.10 wt.-%, 75.+-.5 wt.-%, 50.+-.15 wt.-%,
50.+-.10 wt.-%, 50.+-.5 wt.-%, 25.+-.15 wt.-%, 25.+-.10 wt.-% and
25.+-.5 wt.-% for each of the components.
[0046] In another embodiment of the present invention the inventive
combination may contain components (a) and (b) essentially in an
equieffective ratio.
[0047] In yet a further embodiment of the inventive combination
components (a) and (b) are present in such a weight ratio that the
resulting composition will exert a supra-additive or synergistic
effect upon administration to a patient. Suitable weight ratios can
be determined by methods well known to those skilled in the
art.
[0048] Both components (a) and (b) may also be present in the
inventive combination in ratios deviating from the equieffective
ratio. For, example, each of the components could be present in a
range from 1/50 of the equieffective amount to 50 times the
equieffective amount, from 1/20 of the equieffective amount to 20
times the equieffective amount, from 1/10 of the equieffective
amount to 10 times the equieffective amount, from 1/5 of the
equieffective amount to 5 times the equieffective amount, from 1/4
of the equieffective amount to 4 times the equieffective amount,
from 1/3 of the equieffective amount to 3 times the equieffective
amount, or from 1/2 of the equieffective amount to 2 times the
equieffective amount.
[0049] In another embodiment of the present invention the
components (a) and (b) can be administered in a specific dosage
regimen to treat pain, for example, neuropathic pain. Components
(a) and (b) may be administered simultaneously or sequentially to
one another, in each case via the same or different administration
pathways.
[0050] Another aspect of the present invention is therefore a
method of treating pain, characterized in that components (a) and
(b) are administered simultaneously or sequentially to a mammal,
wherein component (a) may be administered before or after component
(b) and wherein components (a) or (b) are administered to the
mammal either via the same or a different pathway of
administration.
[0051] The term pain as used herein includes but is not limited to
inflammatory pain, neuropathic pain, acute pain, chronic pain,
visceral pain, migraine pain and cancer pain.
[0052] Suitable pathways of administration include but are not
limited to oral, intravenous, intraarterial, intraperitoneal,
intradermal, transdermal, intrathekal, intramuscular, intranasal,
transmucosal, subcutaneous, and rectal administration.
[0053] The inventive combinations are toxicologically safe and are
therefore suitable for the treatment of mammals, particularly
humans including infants, children and grown-ups. Thus, in a
further aspect the present invention relates to a pharmaceutical
composition comprising an inventive combination as described herein
and one or more auxiliary agents.
[0054] In a further aspect the present invention relates to a
pharmaceutical dosage form comprising an inventive combination as
described herein and one or more auxiliary agents. In one
embodiment the inventive pharmaceutical dosage form additionally
comprises caffeine.
[0055] In one embodiment, the pharmaceutical dosage form of the
invention is suitable for being administered orally, intravenously,
intraarterially, intraperitoneally, intradermally, transdermally,
intrathekally, intramuscularly, intranasally, transmucosally,
subcutaneously, or rectally.
[0056] The formulations and dosage forms of the invention may
contain auxiliary agents, for example, carriers, fillers, solvents,
diluents, colorants and/or binders. The selection of auxiliary
agents and of the amounts of the same to be used depends, for
example, on how the drug is to be administered, e.g. orally,
intravenously, intraarterially, intraperitoneally, intradermally,
transdermally, intramuscularly, intranasally or locally, for
example for infections of the skin, of the mucous membranes or of
the eye.
[0057] Suitable auxiliary agents in the context of this invention
include any substances known to persons skilled in the art to be
useful for the preparation of galenical formulations. Examples of
suitable auxiliary agents include, but are not limited to, water,
ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol,
polyethylene glycol, polypropylene glycol, glucose, fructose,
lactose, saccharose, dextrose, molasses, starch, modified starch,
gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose,
methyl cellulose, carboxymethyl cellulose, cellulose acetate,
shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes,
natural and synthetic gums, acacia gum, alginates, dextran,
saturated and unsaturated fatty acids, stearic acid, magnesium
stearate, zinc stearate, glycerol stearate, sodium lauryl sulfate,
edible oils, sesame oil, coconut oil, peanut oil, soybean oil,
lecithin, sodium lactate, polyoxyethylene and polypropylene fatty
acid ester, sorbitan fatty acid ester, sorbic acid, benzoic acid,
citric acid, ascorbic acid, tannic acid, sodium chloride, potassium
chloride, magnesium chloride, calcium chloride, magnesium oxide,
zinc oxide, silicon dioxide, titanium oxide, titanium dioxide,
magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium
phosphate, dicalcium phosphate, potassium bromide, potassium
iodide, talcum, kaolin, pectin, crosspovidone, agar and
bentonite.
[0058] Pharmaceutical formulations (dosage forms) in the form of
tablets, effervescent tablets, chewing tablets, dragees, capsules,
drops, juices or syrups are, for example, suitable for oral
administration. Oral pharmaceutical formulations may also be in the
form of multiparticulates such as granules, pellets, spheres,
crystals and the like, optionally compressed into a tablet, filled
into a capsule, filled into a sachet or suspended in a suitable
liquid medium. Oral pharmaceutical formulations may also be
equipped with an enteric coating.
[0059] Pharmaceutical formulations that are suitable for
parenteral, topical and inhalative administration include but are
not limited to solutions, suspensions, easily reconstitutable dry
preparations and sprays. Suppositories are a suitable
pharmaceutical formulation for rectal administration. Formulations
in a deposit, in dissolved form, for example, in a patch optionally
with the addition of agents to promote skin penetration, are
examples of suitable formulations for percutaneous
administration.
[0060] One or both of the components (a) and (b) may be present in
the inventive pharmaceutical formulation at least partially in
controlled-release form. Moreover, any controlled release/immediate
release combination of said components may also be present in the
inventive pharmaceutical formulation. For example, one or both of
the components may be released from the inventive formulations with
a certain delay, e.g. if administered orally, rectally or
percutaneously. Such formulations are particularly useful for
"once-daily" or "twice-daily" preparations, which only have to be
taken once a day, respectively, twice a day. Suitable
controlled-release materials are well known to those skilled in the
art.
[0061] The pharmaceutical formulations of the invention may be
produced using materials, means, devices and processes that are
well known in the prior art of pharmaceutical formulations, as
described for example in "Remington's Pharmaceutical Sciences", A.
R. Gennaro (ed.), 17.sup.th edition, Mack Publishing Company,
Easton, Pa. (1985), in particular in part 8, chapters 76 to 93.
[0062] In order to obtain a solid pharmaceutical formulation such
as a tablet, for example, the components of the pharmaceutical
composition may be granulated with a pharmaceutical carrier, for
example conventional tablet ingredients such as corn starch,
lactose, saccharose, sorbitol, talcum, magnesium stearate,
dicalcium phosphate or pharmaceutically acceptable gums, and
pharmaceutical diluents, for example water, in order to form a
solid composition that contains the components in homogeneous
distribution. The term "homogeneous distribution" is taken to mean
that the components are distributed uniformly over the entire
composition, so that said composition may easily be divided into
equally effective unit dose forms, such as tablets, pills or
capsules and the like. The solid composition is then divided into
unit dose forms. The tablets or pills of the pharmaceutical
composition according to the invention may also be coated or
compounded in a different manner, in order to provide a dose form
with a controlled release.
[0063] If one of the components is to be released prior to the
other component, for example at least 30 minutes or 1 hour
beforehand, pharmaceutical formulations having a corresponding
release profile may be prepared. An example of such a formulation
is an osmotically driven release system for achieving a delayed
release of one component via a coating that itself contains the
other component which is accordingly released earlier. In a release
system of this kind, which is particularly suitable for oral
administration, at least part, and preferably all, of the surface
of the release system, preferably those parts that will come into
contact with the release medium, is/are semipermeable, preferably
equipped with a semipermeable coating, so the surface(s) is/are
permeable to the release medium, but substantially, preferably
entirely, impermeable to the active ingredient, the surface(s)
and/or optionally the coating comprising at least one opening for
releasing the active ingredient. Moreover, precisely that/those
surface(s) that is/are in contact with the release medium is/are
provided with a coating containing and releasing the other
component. This is preferably taken to mean a system in tablet form
comprising a release opening, an osmotic pharmaceutical composition
core, a semipermeable membrane and a polymer portion that exerts
pressure upon swelling. A suitable example of this kind of system
is the system distributed by ALZA Corporation, USA under the
tradenames OROS.RTM., in particular, the OROS.RTM. Push-Pull.TM.
System, the OROS.RTM. Delayed Push-Pull.TM. System, the OROS.RTM.
Multi-Layer Push-Pull.TM. system, the OROS.RTM. Push-Stick System
and also, in specific cases, the L-OROS.TM..
[0064] Embodiments and examples of osmotically driven release
systems are, for example, disclosed in U.S. Pat. Nos. 4,765,989,
4,783,337 and 4,612,008, the entire disclosure of each of which is
incorporated herein by reference.
[0065] A further example of a suitable pharmaceutical formulation
is a gel-matrix tablet, such as the products developed by Penwest
Pharmaceuticals (for example, under TimeRX). Suitable examples are
provided in U.S. Pat. Nos. 5,330,761, 5,399,362, 5,472,711 and
5,455,046, the entire disclosure of each of which is incorporated
herein by reference. Particularly suitable is a retarding matrix
formulation, with an inhomogeneous distribution of the
pharmaceutically active composition, whereby, for example, one
component can be distributed in the outer region (the portion that
comes into contact with the release medium most quickly) of the
matrix and the other component is distributed inside the matrix. On
contact with the release medium, the outer matrix layer initially
(and rapidly) swells and firstly releases the first component,
followed by the significantly (more) retarded release of the other
component. Examples of a suitable matrix include matrices with 1 to
80% by weight of one or more hydrophilic or hydrophobic polymers as
pharmaceutically acceptable matrix formers. A further example of a
suitable matrix may be inferred from U.S. Pat. No. 4,389,393 the
respective contents of which hereby being incorporated by reference
and forming part of the disclosure of the present invention.
[0066] The amount of the inventive pharmaceutically active
combination to be administered to the patient may vary depending on
different factors well known to those skilled in the art, for
example, the weight of the patient, the route of administration, or
the severity of the illness.
[0067] In a further aspect the present invention relates to the use
of an inventive combination as described herein for the treatment
of pain, said pain preferably including but not being limited to
inflammatory pain, neuropathic pain, acute pain, chronic pain,
visceral pain, migraine pain and cancer pain.
[0068] In another aspect the present invention relates to the use
of an inventive combination as described herein for the preparation
of a medicament for the treatment of pain, said pain preferably
including but not being limited to inflammatory pain, neuropathic
pain, acute pain, chronic pain, visceral pain, migraine pain and
cancer pain.
[0069] In another aspect the present invention relates to a method
of treating pain in a mammal, preferably a human, which comprises
administering an effective amount of an inventive combination as
described herein to the mammal.
Pharmacological Test Methods:
[0070] In vivo Experiments According to Chung
[0071] The weight ratios of components (a) and (b) that will lead
to a supra-additive effect/synergistic effect of the inventive
compositions may be determined in the test of Kim & Chung as
described in Kim S H, Chung J M. An experimental model for
peripheral mononeuropathy produced by segmental spinal nerve
ligation in the rat. Pain 1992; 50: 355-63. Said reference is
hereby incorporated by reference and forms part of the
disclosure.
[0072] Ligatures were applied to the left L5/L6 spinal nerves of
male Sprague-Dawley rats (140-160 g body weight, Janvier, Genest
St. Isle, France). Animals developed tactile allodynia at the
ipsilateral paw. Three to four weeks after the operation the
tactile allodynia threshold baseline (withdrawal threshold) was
measured on the ipsilateral and contralateral hind paw by an
electronic von Frey anaesthesiometer (Somedic, Schweden). After
test and measurement of the baseline,
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride (hereinafter referred to as tapentadol hydrochloride
or tapentadol-HCl), (S)-pregabalin as well as the inventive
combination of tapentadol-HCl and (S)-pregabalin were each
dissolved in 0.9% NaCl solution and injected by the intravenous
(i.v.) route (application volume 5 ml/kg). Animals were randomly
assigned to groups of 10 for each test dose and vehicle (0.9% NaCl
solution) and tactile withdrawal thresholds were tested 0.5 h
before administration and on several time points (0.5, 1 and 3
hours) after intravenous administration. Ipsi- and contralateral
hindpaws were tested. The median of the withdrawal threshold for
each animal at a given time is calculated from five individual
stimulations with the electronic von Frey filament. Withdrawal
thresholds of the injured paws are expressed as % MPE (Maximum
possible effect) comparing predrug threshold of Chung-Animals (=0%
MPE) and control threshold of sham-animals (100% MPE). A cut-off is
set at 100% MPE. The effect of each compound and vehicle is
calculated for each testing time point as interindividual % MPE
value.
[0073] Data (anti-allodynic efficacy (% MPE), ipsi-lateral, paw
withdrawal threshold (g), ipsi- and conralateral) were analysed by
means of a two-factor analysis of variance (ANOVA) with repeated
measures. In case of a significant treatment effect, post hoc
analysis with Bonferroni adjustment was performed. Results were
considered statistically significant if P<0.05. ED50 values and
95% confidence intervals (95% CI) were determined for the
anti-allodynic efficacy (% MPE) at the time of the peak effect for
each drug by regression analysis. The analysis of the results was
carried out via statistical comparison of the theoretical additive
ED.sub.50-value with the experimentally determined ED.sub.50-value
of a so-called fixed ratio combination (isobolographic analysis
according to Tallarida R J, Porreca F, and Cowan A. Statistical
analysis of drug-drug and site-site interactions with isobolograms.
Life Sci 1989; 45: 947-61, which is hereby incorporated by
reference.
Results:
[0074] Tapentadol hydrochloride (0.1, 0.316, 1, 3.16 and 10 mg/kg
i.v.) showed a dose dependent increase in the withdrawal threshold
of the ipsi-lateral hind paw with an efficacy of 94% MPE and an
ED.sub.50-value (95% confidence interval) of 1.65 (1.20-2.35) mg/kg
i.v. calculated from the peak effect vs. control values at 30 min.
after administration.
[0075] (S)-Pregabalin (0.1, 3.16 and 10 mg/kg i.v.) showed a dose
dependent increase in the withdrawal threshold of the ipsi-lateral
hind paw with an efficacy of 67% MPE and an ED.sub.50-value (95%
confidence interval) of 4.20 (3.37-5.43) mg/kg i.v. calculated from
the peak effect vs. control values at 30 min. after
administration.
[0076] Tapentadol hydrochloride and (S)-pregabalin show a potency
difference which amounts to a factor 2.5 based on the ED.sub.50
values 30 minutes after administration. Combinations in a fixed
ratio of 1:2.5 (tapentadol hydrochloride:(S)-pregabalin) were
tested in doses of 0.1 mg/kg+0.25 mg/kg; 0.3 mg/kg+0.75 mg/kg, 1
mg/kg+2.5 mg/kg i.v. tapentadol hydrochloride+(S)-pregabalin,
respectively. These combinations showed a dose dependent increase
in the withdrawal threshold of the ipsi-lateral hind paw. The
highest dose combination tested showed full efficacy with 89% MPE.
Potency was quantified by an ED.sub.50 value (95% confidence
interval) of 0.83 (0.74-0.92) mg/kg i.v. calculated from the peak
effect vs control values at 30 min after administration.
[0077] The results of the isobolographic analysis are summarized in
the following Table 1.
TABLE-US-00001 TABLE 1 Experimental ED.sub.50 values of tapentadol
hydrochloride and (S)-pregabalin and isobolographic analysis of the
interaction between tapentadol hydrochloride and (S)-pregabalin:
Theoretical Experimental ED.sub.50 of the ED.sub.50 of the
combination combination of tapentadol- of tapentadol- tapentadol-
(S)- HCl and (S)- HCl and (S)- HCl pregabalin pregabalin pregabalin
interaction Substance/ 1.65 (1.20-2.35) 4.20 (3.37-5.43) 2.91
(2.28-3.54) 0.83 (0.74-0.92) synergistic ED.sub.50 (p < 0.001)
[mg/kg i.v.] (95% confidence interval) p: Level of statistical
significance
[0078] The experimental ED.sub.50 value (95% confidence interval)
of 0.83 (0.74-0.92) mg/kg i.v. of the inventive combination is
below the theoretical additive ED.sub.50 value (95% confidence
interval) of 2.91 (2.28-3.54) mg/kg i.v. and is statistically
significant (p<0.001) as compared to the line of additivity.
Thus, the interaction of tapentadol hydrochloride and
(S)-pregabalin is synergistic.
[0079] Analysis of contra-lateral paw withdrawal thresholds reveal
significant anti-nociceptive effects of tapentadol hydrochloride
and (S)-pregabalin at 10 mg/kg i.v. while no significant
anti-nociceptive effect was seen at the highest dose of the
inventive combination. Thus, synergistic anti-allodynic activity of
tapentadol hydrochloride and (S)-pregabalin result in reduced
anti-nociceptive side effects.
[0080] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and equivalents thereof.
* * * * *